17-80086090-G-A

Position:

• chr17-80086090-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017950.4(CCDC40):​c.2323G>A​(p.Val775Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,060 control chromosomes in the GnomAD database, including 7,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1255 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5816 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.64

Genes affected

CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

CCDC40 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017687082).
• BP6: Variant 17-80086090-G-A is Benign according to our data. Variant chr17-80086090-G-A is described in ClinVar as [Benign]. Clinvar id is 162851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80086090-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2323G>A	p.Val775Met	missense_variant	14/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.2323G>A	p.Val775Met	missense_variant	14/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2323G>A	p.Val775Met	missense_variant	14/20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.1860G>A		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2323G>A	p.Val775Met	missense_variant	14/18	5		ENSP00000364011.3
CCDC40	ENST00000572253.5	n.950G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17475 AN: 152128 Hom.: 1251 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0880 AC: 21937 AN: 249388 Hom.: 1273 AF XY: 0.0886 AC XY: 11997 AN XY: 135368

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000612

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0855

Gnomad OTH exome AF: 0.0949

GnomAD4 exome AF: 0.0832 AC: 121580 AN: 1461812 Hom.: 5816 Cov.: 32 AF XY: 0.0839 AC XY: 61034 AN XY: 727208

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.0559

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0990

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.0795

Gnomad4 OTH exome AF: 0.0884

GnomAD4 genome AF: 0.115 AC: 17488 AN: 152248 Hom.: 1255 Cov.: 32 AF XY: 0.114 AC XY: 8523 AN XY: 74446

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0825

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0819

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0831 Hom.: 948

Bravo AF: 0.115

TwinsUK AF: 0.0771 AC: 286

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.185 AC: 775

ESP6500EA AF: 0.0846 AC: 711

ExAC AF: 0.0915 AC: 11069

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0858

EpiControl AF: 0.0860

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val775Met in exon 14 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 18.5% (775/4194) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs60684213). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.74	N;N
REVEL	Benign	0.035
Sift	Benign	0.15	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.19	.;B
Vest4		0.080
MPC		0.21
ClinPred		0.0066	T
GERP RS		2.7
Varity_R		0.027
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60684213; hg19: chr17-78059889;